Methods and apparatus for organ support

ABSTRACT

An organ support apparatus includes: (a) a fluid circuit defining upstream and downstream legs adapted to be connected to an organ to be supported; (b) a circulation pump connected to the fluid circuit for circulating a process fluid through the fluid circuit and the organ; and (c) a first waveform generator connected to the fluid circuit for impressing a preselected pressure waveform on the process fluid.

BACKGROUND OF THE INVENTION

This invention relates generally to organ support and bypass processes,and more particularly to methods and apparatus for carrying outperfusion in a controlled manner.

Numerous medical procedures require extraction of a patient's blood,treatment of the blood by processes such as filtering, oxygenation, andthe like, and return of the blood to the patient's body. Examples ofsuch procedures include open heart surgery, organ transplants, membraneoxygenation, and hemodialysis. This type of blood processing is referredto herein as a “bypass” or “body support” process, and typically usespumps with essentially constant pressure output to circulate thepatient's blood through the treatment equipment. Unfortunately, thiskind of flow is much different from the flow provided by a patient'sheart. It has been found that this constant-pressure flow can haveundesirable side effects including brain disorders, blood clotformation, and limited or reduced circulation, especially in flowrestrictive areas. This places undesirable limits on the usage of thistype of equipment.

It is also known that some devices use a similar process to circulate anaqueous organ preservation fluid, such as “Belzer's solution”, throughorgans which have been harvested for transplantation. This actionsustains the organ while it is outside the body by attempting topreserve functioning, and increases the limited “shelf life” oftransplant organs compared to conventional chilled storage. However,known organ support processes encounter the same problems asconventional bypass, namely that the flow pressure characteristics ofthe process fluid are much different than that provided by a patient'sheart. Furthermore, flow which is only “pushed” by a pump is subject tothe formation of gaseous, fibrinothrombocytic, and fat emboli which aredifficult to remove, and which can interfere with flow and cause organdamage.

BRIEF SUMMARY OF THE INVENTION

These and other shortcomings of the prior art are addressed by thepresent invention, which provides a method for perfusing fluid throughorgans and tissues. The system and method described herein act as a“cardiovascular emulator” to provide fluid flow in a manner very similarto a heart.

According to one aspect of the invention, an organ support apparatusincludes: (a) a fluid circuit defining upstream and downstream legsadapted to be connected to an organ to be supported; (b) a circulationpump connected to the fluid circuit for circulating a process fluidthrough the fluid circuit and the organ; and(c) a first waveformgenerator connected to the fluid circuit for impressing a preselectedpressure waveform on the process fluid.

According to another aspect of the invention, an organ support apparatusincludes: (a) a fluid circuit defining upstream and downstream legsadapted to be connected to an organ to be supported; (b) a circulationpump connected to the fluid circuit for circulating a process fluidthrough the fluid circuit and the organ; (c) a first waveform generatordisposed in the upstream leg for impressing a preselected first pressurewaveform on the process fluid before it is delivered to the organ; and(d) a second waveform generator connected in the downstream leg of thefluid circuit for impressing a preselected second pressure waveform onthe downstream pressure applied to the organ.

According to another aspect of the invention, a method of supporting anorgan includes: (a) circulating a process fluid through a fluid circuitcomprising an upstream leg, the organ, and a downstream leg; (b)impressing a preselected first waveform profile upon the fluid flow inthe upstream leg before it enters the organ; and (c) impressing apreselected second waveform profile upon the fluid flow in thedownstream leg.

According to yet another aspect of the invention, a method of supportingan organ includes: (a) circulating a process fluid through a fluidcircuit comprising an upstream leg, the organ, and a downstream leg; and(b) independently controlling the pressure applied to the process fluidat both upstream and downstream connections to the organ.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be best understood by reference to the followingdescription taken in conjunction with the accompanying drawing figuresin which:

FIG. 1 is a schematic view of a organ support apparatus constructedaccording to an aspect of the present invention;

FIG. 2 is a schematic view of a pressure waveform generator of the organsupport apparatus of FIG. 1;

FIG. 3 is a schematic graph of a flow characteristic of the apparatus inoperation;

FIG. 4 is a schematic cross-sectional view of a blood vessel containinga solid embolus therein;

FIG. 5 is a schematic cross-sectional view of a blood vessel containinga gaseous embolus therein.

FIG. 6 is a schematic view of an alternative organ support apparatusconstructed according to an aspect of the present invention;

FIG. 7 is a schematic view of a suction waveform generator of the organsupport apparatus of FIG. 6;

FIG. 8 is a schematic view of an organ support apparatus connected to anorgan outside a patient's body; and

FIG. 9 is a schematic view of an organ support apparatus connected to anorgan inside a patient's body.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings wherein identical reference numerals denotethe same elements throughout the various views, FIG. 1 depicts an organsupport apparatus 10 constructed in accordance with the presentinvention suitable for circulating a fluid through an organ. Theapparatus 10 comprises a fluid circuit defined by plastic tubing oranother suitable type of conduit, with an upstream leg 12 and adownstream leg 14. The apparatus 10 is connected to an organ or otherbody process to be supported, depicted generally at “O”, by an inletline 16 and an outlet line 18. The illustrated example is explained inthe context of providing support for a kidney “K” which is contained inan enclosure 17 and connected to a waste storage container 19 whichreceives a urine flow from the kidney K. However, it will be understoodthat the principles of the present invention are broadly applicable tosupport of many types of organs both inside and outside the body, aswell as different types of body processes. Obviously, the waste storagecontainer 19 would not be needed for other organs. Some of theseapplications are described in more detail below.

The apparatus 10 comprises, in sequential fluid flow order, acirculation pump 20, a perfusate metering array 22, an oxygenator 24, aheat exchanger 26, a bubble trap 28, a fluid waveform generator 30, theorgan O, a sensor array 32, and a biological filter 34 for filteringendogenous or exogenous material from the process fluid (e.g. ahemodialysis filter).

The circulation pump 20 may be any type of pump which can provide therequired flow rates and pressures and is hygienic. The process fluid maybe blood containing cells, plasma, and expanders, or other therapeuticfluids containing complex molecules. Examples of process fluids that maybe used in different processes include aqueous organ preservatives suchas “University of Wisconsin solution”, “Belzer's solution”, whole blood,plasma, serum, crystalloid and non-crystalloid expanders, andoxygen-carrying molecules. The initial process fluid charge volume ofthe apparatus 10 is envisioned to be in the range of about 500 mL toabout 1000 mL. Preferably the circulation pump 20 is a type which doesnot tend to damage these fluid components. Examples of suitable pumpsinclude peristaltic and centrifugal types. The discharge pressure of thepump 20 may be in the range of about 100 to about 600 mm Hg. Optionally,an auxiliary circulation pump 27 may be provided between the perfusatemetering array 22 and the oxygenator 24 and/or between the organ outflowstream and the sensor array 32.

The perfusate metering array 22 comprises a manifold communicating withthe fluid circuit and includes inlets for admitting one or more fluidcomponents into the fluid circuit. Optionally, a pumping apparatus formetering one or more fluid components into the fluid circuit, such asmake-up process fluid, may be incorporated into the metering array 22.The fluid components may be supplied from an external source such as atank or reservoir which is depicted schematically at 60, connected tothe metering array 22 with a supply line 62.

The oxygenator 24 is of a known type which is configured to introduceoxygen into the fluid stream from an external source, such as bottledgaseous oxygen. The oxygenator 24 may be a separate unit or combinedwith the heat exchanger 26, which operates to heat or cool the processfluid to a desired temperature.

The bubble trap 28 is of a conventional type which forces the processfluid past a microporous hydrophobic membrane. Its purpose is to removeany gas bubbles from the process flow that could impede flow in thecirculating loop,

The waveform generator 30 is effective to receive process fluid from theupstream leg 12 of the fluid circuit and reduce the pressure to asuitable value for the organ O, for example about 40 to about 180 mm Hgand to apply a pressure profile thereto, so that the organ O receives apulsating flow which mimics the flow characteristics of a patient'sheart. In the illustrated example, shown in FIG. 2, the waveformgenerator 30 comprises a diaphragm-type pressure regulator 36 having apair of process ports 38 connected to the fluid circuit, a bypass port40 connected to a point upstream of the waveform generator 30, and areference port 42 which is connected to an electropneumatic (E/P)transducer 44 of a known type. Suitable waveform generators of this typeare available from Insight Process Solutions LLC, Hendersonville, N.C.28791 USA. The E/P transducer 44 is in turn connected to a programmableelectronic controller 46 or computer through an input/output (I/O) card48.

The apparatus 10 may include a means for preventing over-pressurizationof the waveform generator 30. In the illustrated example this isprovided by a return line 47 from the output end of the bubble trap 28to the inlet of the circulation pump 20. This relief flow may be aconstant bleed or it may be controlled by a relief valve (not shown) setat a predetermined pressure.

A dump line 64 may be provided, for example downstream of the bubbletrap 28, coupled to a drain or a suitable waste container (not shown).Flow from the fluid circuit to the dump line may be controlled by apurge valve 66, which may be remotely controlled.

Referring again to FIG. 1, the waveform generator 30, which is describedin detail below, receives blood flow from the pump 14 and applies acyclic pressure pulse thereto, as commanded by the controller 46, sothat the organ O receives a pulsating flow which mimics the flowcharacteristics of the patient's heart. An exhaust line 68 routesexhaust fluid from the waveform generator 30 back to an upstream portionof the apparatus, for the example the inlet of the circulation pump 20.

FIG. 3 illustrates an example of the flow characteristics that can beobtained. The dashed line 50 represents the essentially constantpressure output of the circulation pump 20, while the solid line 52represents the total pressure after the fluid passes through thewaveform generator 30. Appropriate feedback signals are provided to thecontroller 46, representative of the output of the apparatus 10. In theillustrated example, the flow has a pulsating pressure with peaks 54occurring at regular intervals. A quasi-square-wave flow characteristicis shown; however, by careful control programming, almost any wave shapedesired can be obtained. This allows the apparatus 10 to closely emulatethe flow characteristics of the patient's heart or to generate specificpreferred waveforms as determined by the physician or technicianinvolved in a particular procedure. It is thought that this willmaximize the “shelf life” of the organ O being transported, or if usedto support the patient directly, will eliminate or reduce undesirableaffects, including brain disorders, normally associated with heart-lungbypass and membrane oxygenator equipment.

The organ enclosure 17 (see FIG. 1) provides physical protection to theorgan (in this case the kidney K). It may be constructed fromsterilizable transparent medical-grade polymer, and is provided withconnections 21 between the artery and vein of the kidney K (for example)and the inlet and outlet lines 16 and 18 respectively. Sensors 76 may beprovided inside the enclosure 17, operably coupled to the artery or veinand effective to measure pressure, flow, and/or temperature of the fluidflowing in and out of the kidney K. There is also a connection 23 to theureter, to allow urine to drain to the waste storage container 19. Thewaste container 19 may be provided with sensors for measuring aspects ofthe urine such as volume, mass, pH, temperature, flow rate, and quantityof metabolites. In the illustrated example, the enclosure includes astructured gelatin 25 that supports the kidney K while evenlydistributing the pressure.

The sensor array 32 includes one or more sensors for evaluating thecondition of the of the process fluid in the fluid circuit, such as flowrate, pressure, temperature, oxygenation levels, gas and/or chemicalcomposition, and the like. Known types of transducers and sensors areutilized to generate signals representative of each measured parameter.

A central controller 49 is provided for the apparatus 10. The centralcontroller 49 includes or more processors and may be a general-purposemicrocomputer of a known type, such as a PC-based computer, or may be acustom processor, or may incorporate one or more programmable logiccontrollers (PLC). The central controller 49 is operably connected tothe individual functional components of the apparatus 10 in order toreceive data and/or transmit commands to each component. For example,the central controller 49 receives data about the process fluidcondition from the sensor array 32. It transmits pressure waveformcommands to the waveform generator 30 to maintain a desired pressurewaveform entering the organ O. The central controller 49 may communicatedirectly with the functional components of the apparatus 10, or throughintermediate devices such as the controller 46 described above. The dataconnections between the central controller 49 and the individualcomponents may be through wired or wireless channels. The centralcontroller 49 may be used for feedback control of the components in theapparatus 10 based on one or more inputs. For example, the compositionof the process fluid may be varied depending on various metabolitelevels in the kidney K. Furthermore, pressure, flow, and/or temperaturedata from the sensors 76 may be used to adjust or “tune” the operatingparameters of the apparatus 10.

The apparatus 10 may be provided with a transceiver 70 coupled to thecentral controller 49. The purpose of the transceiver 70 is tobidirectionally exchange telemetry data with a remote transceiver 72,which may in turn be coupled to a remote controller, computer, or dataserver (not shown). This may be used to monitor the performance of theapparatus 10 and/or to transmit commands to the apparatus 10 remotely.The data connection between the central controller 49 and the remotetransceiver 72 may be wired or wireless.

Optionally, the apparatus 10 may include an electrical stimulator 51coupled to the central controller 49 and to the organ O via electrodes.The electrical stimulator 51 is essentially a controllable electricalpower supply and can be programmed to provide the organ O with arecurrent electrical pulse, for example between about 1.0 and 2.5millivolts. The charge may be positive or negative polarity, with theability to switch polarity. The preprogrammed electrical pulse may betimed either in phase or out of phase with the fluid pulses describedabove. The electrical waveform characteristics of the pulse may bevaried to suit a particular organ. Furthermore, an external input, forexample an ECG or EKG signal (not shown), may be coupled to theelectrical stimulator 51 for aiding in the description of the electricalpulse characteristics and/or pulse timing purposes. The electrical pulseis useful in a known manner for diffusing fluid through the organ O.

Optionally, an imager 74 (visual, UV, IR, etc.) may be used to observethe condition of the organ O through a port in the enclosure 17. Oneexample of a suitable imager is a confocal microscope such as theVIVASCOPE device available from Lucid, Inc., Rochester, N.Y. 14623 USA

With appropriate programming, the central controller 49 may beautomatically flow regulating for different organ tissue masses, thermalconditions that influence vascular elasticity, variable perfusate flowrestrictions at the organ level, and variable fluid characteristics(e.g. viscosity, entrained shear sensitive solids, etc.), whileprecisely maintaining the process fluid flow between narrowly definedsystolic and diastolic pressure set points. This will virtuallyeliminate the potential for permanent capillary damage due to overpressurization of organ vasculature.

FIG. 4 illustrates a cross-section of a blood vessel “V” containing asolid embolus “S” therein. Arrows “P1” and “P2” represent the fluidpressure upstream and downstream of the embolus S, respectively.Typically, solid emboli can be forced downstream using constant orpulsating pressure applied from upstream, i.e. by forcing P1 greaterthan P2. However, as shown in FIG. 5, a gaseous embolus “G” tends toexpand within the vessel V, and cannot be effectively moved byincreasing or pulsing the upstream pressure P1 alone.

Accordingly, FIG. 6 depicts another embodiment of an organ supportapparatus 110 which is generally similar to the apparatus describedabove. It too includes a fluid circuit defined by plastic tubing oranother suitable conduit, with an upstream leg 112 and a downstream leg114. The apparatus 110 is connected to an organ or other body process tobe supported, depicted generally at “O”, by an inlet line 116 and anoutlet line 118. The illustrated example is explained in the context ofproviding support for a kidney “K” which is contained in an enclosure117 suitable for storing or transporting the kidney K. Sensors 176 maybe provided inside the enclosure 117, operably coupled to the artery orvein and effective to measure pressure, flow, and/or temperature of thefluid flowing in and out of the kidney K.

The apparatus 110 comprises, in sequential fluid flow order, acirculation pump 120, a perfusate metering array 122, supply line andreservoir 162 and 166, optional auxiliary pump 127, an oxygenator 124, aheat exchanger 126, a bubble trap 128, return line 147, purge valve 166and dump line 164, an upstream fluid waveform generator 130, exhaustline 168, the organ O, a downstream fluid waveform generator 131, asensor array 132, and a biological filter 134 (e.g. a hemodialysisfilter). A central controller 149 is also provided, and the apparatus110 may include an electrical stimulator 151 similar to the onedescribed above. A transceiver 170, remote transceiver 171, and imager174 may be provided as well.

The downstream waveform generator 131 is shown in FIG. 7. It includes adiaphragm-type device 136 similar in construction to the upstreamregulator and includes a pair of process ports 138 connected to thefluid circuit, and a reference port 142 which is connected to anelectropneumatic (E/P) transducer 144 of a known type. The E/Ptransducer 144 is connected to a programmable electronic controller orcomputer 146 through an input/output (I/O) card 148. The computer 146may be used to control both the upstream waveform generator 130 and thedownstream waveform generator 131.

The downstream waveform generator 131 is effective to precisely regulatethe pressure in the fluid circuit downstream of the organ O (i.e. thesuction-side pressure), independently from the pressure in the upstreamleg 112, regardless of whether the absolute downstream leg pressure isabove or below atmospheric pressure. The flow characteristics aresimilar to those illustrated in FIG. 3, e.g. with suction or pressurepeaks occurring at regular intervals. By careful control programming,almost any wave shape desired can be obtained. The waveform applied bythe downstream waveform generator 131 may be in or out of phase with thewaveform applied by the upstream waveform generator 130, and the pulsesmay be above or below atmospheric pressure. For example, while theabsolute fluid pressure in the entire fluid circuit may be aboveatmospheric pressure, the pressure in the downstream leg 114 may besubstantially lower than that in the upstream leg 112. For example, akidney K could be supplied with a renal artery input pressure of about40 to about 180 mm Hg as described above, with the downstream pressurecontrolled by the downstream waveform generator 131 in the range ofabout 10 to about 50 mm Hg.

The apparatus 10 or 110 may be used to transition an organ O betweenvarious processes in the following manner. When an organ such as akidney K is harvested from a donor, it will be loaded with the donor'sblood and with waste products. When the kidney K is initially connectedto the apparatus, a neutral saline solution or other suitable flushingcomposition may be used as the process fluid and circulated through theapparatus 10 and the kidney K, to flush out the blood and wasteproducts. Using the apparatus 10 provides a much more gentle flushingaction than a conventional flush using manual methods.

While the flushing fluid is circulating, the composition of the of theprocess fluid can be changed at a controlled rate by introducing adesired fluid composition, for example diluted blood containingexpanders, nutrients, or other therapeutic fluids as described above, inthe supply line 62, while opening the purge valve 66 and exhaustingfluid through the dump line 64, to a drain or suitable container. Theinlet flow and the purge flow rate may be set at some percentage of therecirculating flow rate through the fluid circuit, such that eventuallyall of the process fluid will be of the new composition.

In a subsequent step, the process fluid composition can be changed againusing the same transition procedure. For example the process fluid mightbe changed to an organ maintenance, therapeutic, and regenerativechemistry for long-term storage or regeneration of the kidney K.Finally, the process fluid composition may be changed a final time usingthe transition procedure in order to load the kidney K with a recipientpatient's blood type just before implantation.

Regardless of the exact configuration of the organ support apparatusdescribed above, it may be applied in a number of ways. FIG. 8 shows anorgan support apparatus 10 connected to an individual organ O in anenclosure 17 located outside the body as described above. In thisconfiguration, the support apparatus 10 would be used to store or totransport the organ O for transplant. This configuration could also beused for nurturing an organ O to regenerate it, and/or growing an organon a scaffold, by using the metering array 22 to introduce fluidscarrying or seeded with therapeutic and regenerative materials,including cells and biologic growth factors, or other fluids having aregenerative effect on the organ O.

FIG. 9 shows an organ support apparatus 10 connected to an organ O whichis inside a patient “P”, i.e. a human or other animal. In thisconfiguration, one or more blood vessels would be disconnected from thepatient P and connected to the organ support apparatus 10. This has theeffect of isolating the organ O from the rest of the patient's bodywithout requiring removal of the organ or disconnection from vitalphysiologic structures and tissues, and minimizing organ trauma due tohandling procedures and inconsistent blood flow. This configuration isexpected to be especially helpful for patients who require aggressivechemotherapies that can cause severe organ damage, such as the treatmentof malignancies or metabolic toxicities. In such situations, the organscould be isolated and supported for the duration of chemotherapy, andthen reconnected back to the patient's body and placed back “on-line”without having their function impaired and without the need to exposeother organs in the patient “P” to the potentially damaging effects ofchemotherapy (as an example).

The organ support apparatus and method described above greatly reducesorgan tissue related to hypertension (over pressurization) of organcapillaries while effectively perfusing the vascular structure foroptimal preservation and long term functionality.

The foregoing has described systems and methods for organ and bodyprocess support. While specific embodiments of the present inventionhave been described, it will be apparent to those skilled in the artthat various modifications thereto can be made without departing fromthe spirit and scope of the invention. Accordingly, the foregoingdescription of the preferred embodiment of the invention and the bestmode for practicing the invention are provided for the purpose ofillustration only and not for the purpose of limitation.

What is claimed is:
 1. An organ support apparatus, comprising: anenclosure adapted to enclose an organ to be supported and includinginlet and outlet connections configured to be coupled to the organ; afluid circuit defining upstream and downstream legs connected to theinlet and outlet connections respectively; a circulation pump connectedto the fluid circuit for circulating a process fluid through the fluidcircuit and the organ; a first waveform generator disposed in theupstream leg for impressing a preselected first pressure waveform on theprocess fluid before it is delivered to the organ, wherein the firstwaveform generator comprises: a first diaphragm-type pressure regulator;and a first reference pressure source connected to the pressureregulator; and a second waveform generator connected in the downstreamleg of the fluid circuit for impressing a preselected second pressurewaveform on the downstream pressure applied to the organ, wherein thesecond waveform generator comprises: a second diaphragm-type pressureregulator; and a second reference pressure source connected to thesecond pressure regulator.
 2. The organ support apparatus of claim 1wherein the first reference pressure source comprises: a firstelectropneumatic transducer coupled to the first pressure regulator; andan electronic controller coupled to the first electropneumatictransducer and programmed to transmit a signal representative of thepreselected waveform to the first electropneumatic transducer.
 3. Theorgan support apparatus of claim 1 wherein the second reference pressuresource comprises: a second electropneumatic transducer coupled to thesecond pressure regulator; and an electronic controller coupled to thesecond electropneumatic transducer and programmed to transmit a signalrepresentative of the preselected waveform to the first electropneumatictransducer.
 4. The organ support apparatus of claim 1 wherein the fluidcircuit includes at least one filter for removing foreign material fromthe process fluid.